Cardiovascular disease (CVD) is a class of diseases that involves the heart and/or blood vessels. This class of diseases is a leading cause of morbidity and mortality worldwide. The most prominent CVD is atherosclerosis, a condition in which an artery wall thickens as a result of accumulation of fatty materials therein. As atherosclerotic plaques develop they may cause complete closure of the artery lumen, resulting in insufficient blood supply to downstream tissues. Such blockage commonly occurs in coronary arteries or in the arteries of the brain, resulting in myocardial infarction or stroke, respectively.
Lipidic materials, including cholesterol, are transported in the circulatory system by lipoproteins, of which two major classes are high density lipoproteins (HDL) and low density lipoproteins (LDL). HDL is commonly referred to as “good cholesterol” as it operates to remove excess cholesterol from the arteries and transport it to the liver. LDL is commonly referred to as “bad cholesterol”, as it delivers cholesterol to the tissues, thus contributing to cholesterol accumulation in arterial macrophages, a first step in the development of atherosclerotic plaques. Patients with cholesterol levels higher than normal, in particular LDL cholesterol, a condition commonly referred to as hypercholesterolemia, are at high risk of developing atherosclerosis. One of the ways to control hypercholesterolemia is to limit dietary cholesterol intake. However, in many patients, controlling dietary cholesterol intake is not sufficient in reducing cholesterol levels. Medications such as statins are commonly administered to patients with hypercholesterolemia in order to lower the risk of CVD.
Statins are compounds which inhibit the enzyme HMG-CoA reductase, a key enzyme in the de novo synthesis of cholesterol, thereby lowering the production of cholesterol within the cells (A. Rosanoff 2004). This causes increased cholesterol uptake from the bloodstream to the cells, thus lowering serum cholesterol and the risk of CVD. The first statin marketed was lovastatin, which was isolated from the fungus Aspergillus terreus and marketed by Merck & Co. Other statins were identified in naturally occurring fungi such as oyster mushrooms and red yeast rice. After lovastatin, other statins were developed and their use became common among hypercholesterolemia patients and patients at high risk of CVD. Additional statins include atorvastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Statins are now the most prescribed drugs worldwide.
In addition to lipoprotein concentration in the blood, lipoprotein oxidation also plays a major role in the development of atherosclerosis. Oxidized LDL (oxLDL) is taken up by arterial macrophages in a non-controlled fashion, thus leading to accumulation of cholesterol in the arteries (B. Fuhrman 2002). In addition, beneficial anti-atherogenic effects of HDL are impaired upon its oxidation (Smith 2010). Antioxidants that reduce oxidation of LDL and HDL were found to have an in vivo effect in reducing atherosclerosis. For example, a mixture of antioxidants lycopene, resveratrol, catechin and vitamins E and C reduced atherosclerosis in transgenic mice (L. Verschuren 2011).
Although statins and antioxidants were shown to have a beneficial effect on atherosclerosis and on coronary heart disease, when statins were administered in combination with some antioxidants, not only did there appear to be an absence of benefit from the combinations relative to the use of each component alone, but the components of the combinations appeared to interfere with each other. The combinations appeared less effective as anti-atherosclerotic agents than the statins and the antioxidants when not administered in combination. For example, in patients with low HDL, beneficial effects of simvastatin and niacin were blunted when compared to a group of patients receiving simvastatin/niacin in combination with the antioxidants beta-carotene, vitamin C, vitamin E, and selenium (M. C. Cheung 2001). Another study showed that patients receiving atorvastatin in combination with the antioxidant vitamin E experienced less of a reduction in the expression of pro-inflammatory cytokines than patients receiving atorvastatin alone (D. Tousoulis 2005).